Poster abstracts
Poster number 18 submitted by Manie Brema
Immunomodulatory mechanism of T cells and Myeloid cells in dystrophic hearts
Manie Brema (Department of Physiology and Cell Biology, OSU), Arden Piepho, PhD (Department of Physiology and Cell Biology, OSU), Esther Silver (Department of Physiology and Cell Biology, OSU), Saloni Sachdeva , Katherine E. Miller, PhD (Nationwide Childrens Hospital ), Jill Rafael-Fortney, PhD (Department of Physiology and Cell Biology, OSU)
Abstract:
Duchenne muscular dystrophy (DMD) results from dystrophin deficiency and is characterized by progressive loss of striated muscle, accompanied by inflammation and replacement fibrosis. DMD patients develop dilated cardiomyopathy in their mid-teens, progressing into heart failure, which is now the leading cause of death. However, there was a lack of appropriate DMD models recapitulating contractile dysfunction to study dystrophic hearts. Our lab established the first severe DMD cardiomyopathy model, Fiona/dko, where contractile function is reduced indicative of heart failure. Fiona/dko mice contain fibrosis and chronic inflammation, but the contribution of inflammation in dystrophic cardiac pathology remains poorly characterized. Our lab demonstrated unique immune profiles in dystrophic hearts featuring both T cell and myeloid cell infiltration that peak early in disease progression, in contrast to predominantly myeloid cell infiltration in dystrophic skeletal muscles. Pro-inflammatory genes were upregulated in Fiona/dko whole-heart transcriptomes; however, whether transcriptomic signatures in myeloid cells or T cells are altered is unknown. We performed transcriptomic analysis of CD3+ T cells and CD11b+ myeloid cells to define the immunomodulatory mechanisms that regulate severe pathogenesis in Fiona/dko hearts. Differential gene expression and pathway analyses revealed that CD11b+ myeloid cells exhibit transcriptional repression of potassium channel activity, cell adhesion molecules, and chemokine signaling, thereby modulating inflammatory recruitment and activation state. T cells showed enrichment of NK-mediated cytotoxic pathways, suggesting a cytotoxic immune phenotypic switch. These data suggest a coordinated mechanism by which myeloid cells shift the inflammatory environment, and T cells adopt effector functions. This work provides insights into inflammatory mechanisms of DMD cardiomyopathy and potential therapeutic strategies to improve cardiac outcomes.
Keywords: DMD cardiomyopathy, T cells , Myeloid Cells